Detailed understanding of developmental mechanisms is essential to diagnose and treat congenital malformations. A common group of congenital malformations are those that affect limb development. We have defined underlying cause of one such malformation, nail-patella syndrome (NPS) that affects the development of the nails, patella, and elbow. NPS is caused by mutations in the LIM-homeodomain transcription factor LMX1B. Our studies in the mouse have indicated that Imxlb is expressed specifically in the dorsal limb bud mesenchyme where it acts as a selector gene to specify dorsal cell fates. How Imxlb expression is restricted to and maintained in the dorsal limb bud mesenchyme is poorly understood as is the mechanism(s) by which Imxlb regulates dorsal-ventral patterning. In the proposed research we will address three main issues. First, we will employ conditional gene targeting of Imx1 b to determine whether specific subsets of mesenchymal tissues coordinate musculoskeletal patterning of the limb. Second, we will examine mechanisms that are responsible for the dorsal-specific expression of Imxlb by lineage tracing and transgenic analysis. Finally, we will test the ephrin/Eph signaling pathway as a candidate effector of Imxlb in regulating dorsal-ventral limb bud development. Taken together, these experiments will provide significant insight into how vertebrate selector genes function to coordinate regulation of a complex developmental program. Lmxlb activity is also required in other tissues of the body both during development and in the adult. From studies in mice and humans we know that Imx1 b is required for proper functioning of the kidney and outflow tract of the eye as well as for proper development of the dopaminergic and serotonergic systems of the CMS. The proposed research will provide information about the function of Imxlb in limb development, but will also shed light into how Imxlb regulates kidney, eye, and brain development. As individuals with mutations in LMX1B are at risk for renal failure and glaucoma our research will also impact important heath concerns. [unreadable] [unreadable] [unreadable]